INTRODUCTION:

Pre-anaesthetic medications are used with the object of making anaesthesia safer and easygoing to the patient. The goal is to mitigate anxiety by inducing sedation, to help in easy induction and also to counteract the adverse effects of anesthetic drugs such as nausea, vomiting, and excess salivation. These medications also reduce pre and post-operative pain and suppress respiratory secretions and reduce reflex excitability ^[1-2].

Children as well as their parents remain very stressful during the pre-operative period due to anxiety, fear, nervousness related to the surgery ^[3].

So the pre-anesthetic medications used in modern anaesthetic practice aims to relieve anxiety and thereby make the experience of anaesthesia and surgery more pleasant and less traumatic^[4].

Clonidine is a α₂ adrenergic agonist, found to have analgesic, anxiolytic, and sedative properties in addition to antihypertensive effect ^[5]. This drug acts as an effective pre-anesthetic medication in adult and pediatric population and also reduces the requirements for anesthetics during surgery as well as post-operative analgesics ^[6-10]. Scientists focused on the analgesic properties of the clonidine. It is mentioned that intravenous administration of clonidine after spinal surgery provides better post-operative analgesia ^[10]. Oral administration of clonidine provides better pain relief in minor orthopedic surgery ^[11]. Pretreatment with clonidine decreases the minimum alveolar concentration of the inhalational agents for induction, endotracheal intubation, and maintenance of anesthesia ^{[5-6, 12]}. Clonidine also benefits the patient by a decreased postoperative incidence of nausea, vomiting, shivering, emergence delirium, and also by a reduction of postoperative requirements for opioids ^[13-15]. Other benefits of clonidine include prevention of intraoperative hemodynamic instability and changes in the hemodynamic parameters ^[16]. This medication has a slow onset of action (0.5-1hour) and a long duration of half-life for about 12hours ^[17-18].

Study on the analgesic property of clonidine showed that the duration of analgesia with caudal bupivacaine was increased by addition of clonidine in children undergoing umbilical surgery ^[19]. This is supported by Lyons et al., 1996 ^[20] who mentioned that addition of low dose clonidine to the analgesic regime can produce a dramatic reduction in morphine consumption with an improvement in ventilatory, gastrointestinal and psychological functions. Thus, the efficacy of clonidine as a pre-anesthetic analgesic is enormous.

Multiple studies all over the world have been performed to scrutinise the effect of clonidine in pediatrics patients. However, in Bangladesh, it is found that most of the studies were performed in adults. It is also not a common practice to use Clonidine among children prior to surgery and as such no study was done previously with clonidine giving prior to surgery in pediatric patient. Considering that fact, we undertook the current study to investigate the effectiveness of oral clonidine premedication provides post-operative pain relief in children. The objective of this study was to assess the efficacy of oral clonidine as pre-anaesthetic medication in reduction of post-operative pain in children. We compared the post operative pain between patients receiving clonidine and the patients of control group (without clonidine).

METHODS:

This prospective study was carried out in a private medical college hospital in Bangladesh from April 2010 to September 2011. Parental informed consent was taken before starting the trial. The patients were selected based on American Society of Anaesthesiologist (ASA) classification system. Children of ASA physical status I, between 3months -3 years of age, undergoing chiloplasty and palatoplasty surgery were included in the study to evaluate the analgesic effect of oral clonidine premedication. This study was approved by the ethical committee of the Medical College and Hospital.

Total 60 patients were randomly selected and they were assigned into two groups with 30 children per group; the control group was given juice or milk as the placebo and the clonidine group was given clonidine (4 μg/kg) in juice or milk, 60 minutes before the estimated time of induction of anesthesia. All children in the current study also received atropine 0.03 mg/kg per oral in juice or milk at the same time.

Anesthesia was induced by thiopental sodium and maintained with halothane and nitrous oxide (60%) in oxygen. All patients underwent tracheal intubation facilitated with vecuronium 0.1 mg/kg I/V and muscle relaxation was maintained at 70% depression of twitch tension with intermittent vecuronium as required.

Controlled mechanical ventilation was adjusted to maintain partial pressure of end tidal CO₂ between 30 and 40 mm Hg. Arterial hemoglobin oxygen saturation was (SPO₂) measured with this monitor was constantly maintained at 99%. Body temperature was maintained between 36.6 and 37.7^οC to avoid the stress from hypothermia. Post operatively the trachea was extubated in the operating room after residual neuromuscular block has been antagonized with neostigmine 0.05 mg/kg and atropine 0.02 mg/kg I/V.

All children transferred to the post operative room, where they could see one of their parents. No children received anti emetics in the post operative period.

The level of sedation in the operation room was assessed with a three point sedation scale (1= tearful/combative; 2= alert/aware; 3=drowsy/sleeping) as described ^[9].

Pre and post-operative blood pressure (BP), heart rate (HR) and respiratory rate (RR) were measured following the standard procedure. HR and BP were recorded immediately before induction of anesthesia (pre-induction), before the start of surgery (pre-operative) and during the operation (intra operative). During operation, HR and BP were recorded at every 10 minutes interval. Post operative hemodynamic variables were measured at every 10minutes interval for the initial 2hour, then at every 20 minutes interval for the next 3 hour (2-5 hour post-operative) and then at 30 minutes interval for the subsequent 7 hour (from 5 to 12hour post-operatively).

The definitions of mild effects on hemodynamic end points for the intra and postoperative managements were as follows: tachycardia, an increase in heart rate of 20% or more over ward baselines and bradycardia, a reduction of HR by 20% or more. Hypertension was defined as intra or post operative changes in systolic BP greater than 20% compared with ward levels The definition of hypotension and bradycardia as side effects were systolic BP <70 mm Hg and HR <60 bpm.

The SPO2 was continuously recorded from premedication until 12 hour after surgery. Respiratory rate was observed during the first 60 minutes after completion of anesthesia. This time period is particularly important as hypoxia can develop during this time ^[21]. Extreme respiratory depression and hypoxemia were defined as RR<12 breaths/minute and SPO2 <90% respectively. We gave supplementary oxygen by mask in which SPO2 was less than 90%.

Pain was rated by an independent observer using the objective pain scale (OPS) for post operative pain assessment in children ^[22-23]. The parameters used in this scale are systolic blood pressure, crying, movement, agitation and complains of pain. The scale is described in Table I. The minimum score is 0 and the maximum score is 10. However, the maximum score is 8 in cases if the child is too young to complain. In this study we took the highest score as 8 because of the age group of the children is 3months to 3 years who could not verbalize the pain. Pain free denotes those children who scored 0 (no pain) over the specified time period. In this study, pain assessment was made post-operatively immediately after awakening in the operating room and 0.5,1,2,3,4,5,6,8 and 12 hours thereafter by a single independent observer. Children with OPS score of 4 or greater received a diclofenac suppository (12.5 mg) as a rescue analgesic.

Table I: Objective Pain Score:

Observation	Criteria	Points
Blood pressure	±10% of preoperative	0
	>20% preoperative	1
	>30% preoperative	2
Crying	Not crying	0
	Crying but respond totender loving	1
	Crying and does notrespond to tender loving	2
Movements	None	0
	Restless	1
	Thrashing	2
Agitation	Patient asleep or calm	0
	Mild	1
	Hystorical	2
Verbalizes Pain	Asleep or no verbalization of pain	0
	Cannot localize pain	1
	Localizes pain	2

The efficacy of clonidine was assessed in terms of the highest OPS score, the percentage of pain free (OPS=0) children during the 12 h pos operative period, and the overall number of patients requiring analgesic rescue therapy.

Data were compiled and expressed as the mean and SD. Statistical analysis was conducted by doing unpaired T-Test. P value of <0.05 was considered statistically significant.

RESULTS:

Table I is showing the parameters used in the objective pain scale. Table II is showing the comparison between the two groups with respect to age, weight, type of operation, pre medication time, surgical time, anesthesia time, time to extubation and time to eye-opening . There was no significant difference observed between the groups. All children had recovered to the same degree on arrival in the wards.

Children receiving clonidine were better managed for the analgesic effect and remain pain free compared to the control group. Only 6.66% (2 out of 30) children required rescue analgesic (diclofenac suppository) in the clonidine group whereas 83.3% (25 out of 30) children required rescue analgesic during the post-operative period (P<0.001). The highest OPS score was lower in the clonidine 4μg/kg treated group than in those treated with placebo. The score was 3.4 (range: 0-8) in the clonidine group while in the placebo group the score was 4.5 (range: 3-8) However there was no significant difference was observed (P>0.05) (Table III).

Table II: Clinical characteristics of the study group

Groups	Control (n=30)	Clonidine 4 μg/kg(n=30)
Age(months)	18.66±10.29	16.5±11.8
Weight(kg)	10.51±2.96	9.73±2.72
Premedication Time(min)	102.26±1.83	103.16±2.0
Surgical Time (min.)	71.16±17.5	71.5±14.6
Anesthesia Time(min.)	94.6±19.95	94.8±16.05
Time to Extubation(min.)	7.56±1.07	7.4±1.18
Time to eye opening (min.)	10.26±1.65	10.13±1.63
Type of surgery
Chiloplasty	15	15
Palatoplasty	15	15

For all variables, p>0.05 between groups. Values are expressed as mean± SD or median (range) of post operative recovery scores.

Table III: Overall number of patients(n and%) required post-operative analgesic “Rescue” therapy and Highest Objective Pain Score (OPS) (median and range) in the two groups

Control

(n=30)

Clonidine 4μg/kg

(n=30)

0-12 h after surgery(overall)

25(83.33%)

02 (6.66%)

Overall highest OPS score

4.5(3-8)

3.4(0-8)

Table IV: Perioperative vital sign

	Control	Clonidine 4μg/kg
WARD baseline
SBP	85.26±5.26	*89.16±6.4(P=2.58)
DBP	53.16±3.27	*55.3±3.12(P=2.60)
HR	120±14.92	122.5±8.4(P=0.80)
RR	26±4.20	28±4.38(P=1.18)
Pre induction
SBP	100.6±5.9	*95±8.27(P=2.97)
DBP	60.3±3.12	59.5±3.26(P=0.97)
HR	134±12.8	*126.2±13(P=2.33)
Pre operative
SBP	100.26±5.39	94.3±8.8(P=1.74)
DBP	57.4±3.23	**54.5±3.46(P=3.37)
HR	112.83±13.34	*104.3±9.9(P=2.54)
Intra operative
SBP	92.8±4.64	*89.6±6.7
DBP	57.2±3.43	*53.5±3.79
HR	110.2±13.4	*100.8±12.13
Post operative
0-2h after surgery
SBP	102.96±8.8	**92.6±6.6
DBP	63.1±3.6	**55±3.65
HR	120.5±12.38	**108.6±11.4
RR	27.7±3.14	*25.8±4.28
2-12h after surgery
SBP	90.16±5.3	87.5±6.05
DBP	56.63±3.14	*54±2.4
HR	118.9±14.95	115.9±9.2
RR	28.7±3.14	*26.5±4.09

Values are expressed in mean±SD (n=30 for each group)

SBP=systolic blood pressure, DBP=diastolic blood pressure, HR= heart rate, RR=respiratory rate, SPO2 = arterial hemoglobin oxygen saturation;

*P<0.05 versus WARD baseline within groups and versus control.

**P<0.01 versus control.

Intra operative BP and HR were lower in the clonidine 4 μg/kg group than the in the control group (Table IV). These hemodynamic variables were lower in the clonidine group than in the control group during the early phase of post operative period. There after heart rate remained low in children receiving clonidine 4μg/kg.

During the post operative period, RR was also slower in the clonidine group than the in the control group. No children in the clonidine group experienced severe hypotension, bradycardia, respiratory depression according to our arbitrary extreme definitions and none of these children received any post operative pharmacological treatment for these complications. No children were suffered from mild hypotension and only 3 children developed mild bradycardia in the clonidine group. However, these differences in post operative vital signs among the two groups were of little clinical significance.

DISCUSSION:

The current study was done to find out the efficacy of oral clonidine premedication to reduce post operative pain in children. A total of 60 children (30 control and 30 received clonidine 4μg/kg) undergoing palatoplasty and chiloplasty were selected randomly for the study.

The findings in this study support the beneficial effects of clonidine. It was observed that clonidine 4 μg/kg provided better sedation score (sedation scores of 1, 2 and 3 for 2, 12 and 16 children respectively than did placebo (sedation scores 1, 2 and 3 for 20, 10 and 0 respectively). Total 16 children experienced scale 3 sedation which means they were drowsy or in sleep compared to none in the placebo group. One study identified that 63% of patients receiving oral clonidine 4 mg/kg were asleep or drowsy within 60–90 minutes and could be easily separated from their parents ^[24]. Another study indicates that oral clonidine 3μg/kg produces effective sedation in children which is comparable to diazepam 0.2mg/kg ^[25]. We know that sedation is important as it leaves good experience to the children and as well as to the parents. Otherwise the trauma related to the operation can leave subsequently some significant effect on the child.

Similarly post-operative analgesia was also less in the clonidine group than the placebo group and requirement for supplementary analgesia was reduced in children of clonidine group compared to control which is significant. More children receiving clonidine were pain free over the entire 12 hour period than those of the control group. It is reported ^[26] that clonidine produces good sedation and causes less effect on psychomotor functions and therefore it can be used as a premedicant in children. Due to the analgesic and sedative effect of clonidine, recently this drug is used as an analgesic and sedative medication in the Intensive Care Unit (ICU) ^[27] and forms a part of the ICU protocol in UK ^[28].

Though previous study showed that the analgesic effect of clonidine is less potent when administered via oral route than extradural route ^[29], oral clonidine 4μg/kg premedication is effective for post-operative pain relief, especially in conditions where administration by epidural route is not feasible because of upper dermartomes such as ophthalmologic, otolaryngologic and facial surgery cases ^[9]. Oral clonidine 4μg/kg premedication reduces the post operative pain and use of supplementary analgesia in patient underwent minor surgery^[9]. Moreover, oral administration is the most readily acceptable way of giving the drug to children. In addition, IV access may not always be established for minor surgery ^[30]. Considering all these aspects, clonidine is found as a better option for pain relieve in case of children.

The prophylactic use of analgesics may decrease the post operative requirements and reduces the noxious input to the central nervous system. Oral premedication may induce a significant effect on pain management and advantageous according to the concept of “pre-emptive analgesia” where combination of NSAID, opioids, local anesthetics and other drugs are used ^[31]. A major advantage of clonidine over opioid analgesic is its lower potential for respiratory depression and as clonidine and opioid act on different sites; a combination of these drugs can provide additive pain relief ^[9].

Clonidine is reported to cause the side effects of hypotension along with bradycardia ^{[14, 17]}. However in our study, no children in the clonidine group experienced severe or mild hypotension. Only 3 children developed mild bradycardia in the clonidine group with no severe bradycardia. However, these differences in post operative vital signs among the two groups were of little clinical significance.

In the current study atropine has been used by all patients. We think that the hemodynamic changes may have been ameliorated by concomitant use of oral atropine. It is mentioned that routine atropine administration along with clonidine negates the adverse effects like bradycardia and hypotension ^[18]. The absence of severe pre and post operative severe side effects of clonidine will encourage us to use clonidine in children undergoing surgery in the future.

The current study showed that oral clonidine 4μg/kg reduced post-operative pain score and requirement for supplementary analgesic in children compared to control group and did not show severe adverse effects. These data suggest that oral clonidine premedication is a possible approach to post-operative pain relief in pediatric minor surgery. Since the degree of post-operative pain depends upon the severity of the surgical procedure, post-operative analgesia by oral clonidine in major surgery deserves further well designed prospective study. Additional studies are also required to compare analgesic effect by oral and other routes of administration of clonidine in this clinical setting.

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Received on 22.04.2013 Modified on 10.05.2013

Research J. Pharm. and Tech 6(6): June 2013; Page 632-636

Efficacy of Oral Clonidine as Pre-Anesthetic Medication in Reduction of Post-Operative Pain in Children- A Randomized Controlled Trial